Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul, Korea.
BMC Cancer. 2020 Oct 15;20(1):1001. doi: 10.1186/s12885-020-07471-3.
Histone deacetylase inhibitors (HDACIs) have distinctive epigenetic targets involved in hepatocarcinogenesis and chemoresistance. A recent phase I/II study reported the possibility of HDACI as a chemosensitizer in sorafenib-resistant patients. In this study, we evaluated whether CKD-5, a novel pan-HDACI, can potentiate the efficacy of sorafenib.
The anticancer effect of CKD-5 with and without sorafenib was evaluated in vitro using an MTS assay with human HCC cells (SNU-3058 and SNU-761) under both normoxic and hypoxic conditions. Microarray analysis was performed to investigate the mechanism of cell death, which was also evaluated by small interfering RNA (siRNA) transfection and subsequent immunoblot assays. In vivo experiments were conducted using two different murine HCC models. C3H mice implanted with MH134 cells and C57BL/6 mice implanted with RIL-175 cells were treated with weekly CKD-5 with and without sorafenib for 2 weeks.
CKD-5 treatment significantly suppressed human HCC cell growth in both normoxic and hypoxic conditions. Microarray analysis and real-time PCR showed that CKD-5 treatment significantly increased peripherin expression in HCC cells and that downregulation of peripherin by siRNA decreased CKD-5-induced apoptosis. The combination of CKD-5 and sorafenib decreased cell viability more effectively than sorafenib or CKD-5 monotherapy in human and murine HCC cells. The effectiveness of the combination therapy was consistently demonstrated in the animal models. Histological and biochemical analyses demonstrated good tolerance of CKD-5 plus sorafenib in vivo.
CKD-5 may enhance sorafenib efficacy through epigenetic regulation. The combination of CKD-5 and sorafenib might be a novel therapeutic option for the treatment of HCC.
组蛋白去乙酰化酶抑制剂（HDACIs）具有独特的表观遗传靶点，参与肝癌的发生和化疗耐药。最近的一项 I/II 期研究报告了 HDACI 作为索拉非尼耐药患者化疗增敏剂的可能性。在这项研究中，我们评估了新型泛 HDACI CKD-5 是否可以增强索拉非尼的疗效。
在常氧和低氧条件下，使用 MTS 测定法评估 CKD-5 与索拉非尼联合应用对人肝癌细胞（SNU-3058 和 SNU-761）的抗癌作用。通过微阵列分析研究细胞死亡的机制，并通过小干扰 RNA（siRNA）转染和随后的免疫印迹分析进行评估。使用两种不同的小鼠肝癌模型进行体内实验。用 MH134 细胞植入 C3H 小鼠和用 RIL-175 细胞植入 C57BL/6 小鼠，每周用 CKD-5 联合或不联合索拉非尼治疗 2 周。
CKD-5 治疗在常氧和低氧条件下均显著抑制人肝癌细胞的生长。微阵列分析和实时 PCR 显示，CKD-5 处理显著增加 HCC 细胞中外周蛋白的表达，外周蛋白的 siRNA 下调降低了 CKD-5 诱导的细胞凋亡。CKD-5 与索拉非尼联合用药比索拉非尼或 CKD-5 单药治疗更有效地降低人源和鼠源 HCC 细胞的细胞活力。在动物模型中一致显示出联合治疗的有效性。组织学和生化分析表明 CKD-5 联合索拉非尼在体内具有良好的耐受性。
CKD-5 可能通过表观遗传调控增强索拉非尼的疗效。CKD-5 与索拉非尼的联合治疗可能是治疗 HCC 的一种新的治疗选择。
